PROJECT SUMMARY: Integrase strand transfer inhibitors (InSTI), such as dolutegravir (DTG) and bictegravir (BIC), have high antiviral potency against HIV-1, excellent safety and tolerability, and a high barrier to resistance. It is a high priority to promote the availability and rational use of InSTI in adults and children with HIV, including those with tuberculosis (TB). South Africa has the highest rates of HIV and TB co-infection in the world-- among patients with TB, 50-80% have HIV. Rifampicin (RIF), an essential first-line TB drug, is a potent inducer of metabolizing enzymes and transporters, causing drug interactions that limit HIV-TB co-treatment options. In adults, DTG, now recommended by World Health Organisation (WHO) as the preferred first-line antiretroviral for the treatment of HIV-1, can be given together with TB treatment, provided the dose is doubled (to 50 mg twice daily) to mitigate the drug interaction. While DTG dosing has now been established for children down to a weight of 20kg, no data exist to guide dosing for young children with TB on RIF-containing treatment. BIC, co- formulated with emtricitabine and tenofovir alafenamide (BIC/FTC/TAF, Biktarvy) was recently shown to be non-inferior to DTG-based treatment, with no emergence of resistance in Phase 3 trials. However, no data exist in patients with HIV-associated TB on BIC/FTC/TAF efficacy, safety, or pharmacokinetics (PK) when it is given twice daily with RIF. In HIV-negative healthy volunteers, BIC trough concentrations were reduced by 80% with RIF (but remained 3-fold higher that the protein adjusted effective concentration (paEC95). In another study, TAF even with RIF produced higher concentrations of intracellular tenofovir-diphosphate (TFV-DP), the active moiety, than when tenofovir disoproxil fumarate (TDF) was given alone. The specific aims of the study are therefore 1) To assess the efficacy, safety, and PK, of twice daily, co-formulated BIC 50mg/FTC 200mg/TAF 25mg in HIV positive ART-nave adult patients with TB who are receiving a RIF-based regimen. 2) To determine the PK and safety of DTG 50mg twice daily in children (20-35kg) who are taking a RIF-containing regimen for the treatment of TB. The proposed studies are timely and will generate knowledge needed to support evidence-based use of InSTI in adults and children with HIV-associated TB who are taking RIF- based treatment. Both these studies are high impact. Firstly, South Africa and KwaZulu Natal in particular are in the epicenter of the TB-HIV co-epidemic- the majority of patients with TB also have HIV. Secondly, there are no data to support the safety and efficacy of Biktarvy twice daily for the treatment of HIV-1 infection in patients with TB on RIF co-treatment and it is unlikely that this potent, safe drug with a high genetic barrier to resistance, that may provide effective future ART treatment options, will be made available in Africa if it cannot be used in patients with TB. Thirdly, there are no published data to support dose recommendations for DTG among children receiving TB treatment (particularly in the proposed weight-band). HIV-TB co-treatment options are extremely limited in children, making this an area of critical unmet medical need.